Peritoneal macrophage depletion by liposomal bisphosphonate attenuates endometriosis in the rat model.
BACKGROUND
Activation of macrophages is central to the implantation of endometriosis (EM). We examined the hypothesis that macrophage depletion by intraperitoneal (IP) injection of liposomal alendronate (LA) could result in EM attenuation in a rat model, thus supporting the notion of the pivotal role of macrophages in EM pathology.


METHODS
In this study, 90 rats were subjected to an EM model and were divided randomly into seven groups: five groups were treated by 4x once-weekly IP injections of LA (0.02, 0.1, 1, 5 or 10 mg/kg) and the other two groups received saline injections (control) or empty liposomes. Sham-operated rats also received empty liposomes. Depletion of circulating monocytes was determined by flow cytometry analyzes of blood specimens. Four weeks after the initial surgery, the number, size and weight of implants were recorded, adhesions were graded, macrophage infiltration was assessed and the peritoneal fluid was analyzed for monocyte chemotactic protein 1 (MCP-1) and tumor necrosis factor alpha (TNFalpha).


RESULTS
Monocyte depletion following IP LA administration resulted in an inhibitory effect on the initiation and growth of EM implants, as expressed by implantation rate, adhesion scoring, implants' size and weight (>0.1 mg/kg LA, P < 0.05). Reduced numbers of infiltrating macrophages were observed in implants of the 1 mg/kg LA group. Peritoneal fluid MCP-1 levels were negatively correlated with LA dose (P < 0.001), whereas no significant correlation could be found for TNFalpha.


CONCLUSIONS
Macrophage depletion using IP LA has been shown to effectively inhibit the initiation and growth of EM implants, in a rat EM model. The clear dose-response effect may be viewed as a confirmation of the validity of the concept and encourages further study.
Haber
E
E
Faculty of Medicine, Department of Pharmaceutics, School of Pharmacy, The Hebrew University of Jerusalem, PO Box 12065, Jerusalem 91120, Israel.
Danenberg
H D
HD
Koroukhov
N
N
Ron-El
R
R
Golomb
G
G
Schachter
M
M
D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D018932:Chemokine CCL2 / Q000032:analysis; D016207:Cytokines / Q000502:physiology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004715:Endometriosis / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D008081:Liposomes; D017737:Macrophages, Peritoneal / Q000187:drug effects*; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
D050071:Bone Density Conservation Agents; D018932:Chemokine CCL2; D016207:Cytokines; D008081:Liposomes; D014409:Tumor Necrosis Factor-alpha; D019386:Alendronate